The present invention relates both to a process for obtaining sodium or potassium salts of 4-carboxy-3-hydroxy-5-mercapto-isothiazole which are compounds usable in the production of Cefotetan, and to new compounds obtained by the process.
Cefotetan is a semi-synthetic injectable cephalosporin of formula 
According to the method described in U.S. Pat. No. 4,263,432 and in Chem. Pharm. Bull. 28, 2629-2636 (1980), Cefotetan is obtained from 7xc3xa1-(4-carboxy-3-hydroxyisothiazol-5-yl)thioacetamido-7xc3xa1-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-xc3x843-cephem-4-carboxylic acid of formula 
which is itself prepared by reacting 7xc3xa1-bromoacetamido-7xc3xa1-methoxy-3-(1-methyltetrazol-5-yl) thiomethyl-xcex943-cephem-4-carboxylic acid with a trisodium 4-carboxy-3-hydroxy-5-mercapto-isothiazole of formula 
where R1xe2x95x90R2xe2x95x90R3xe2x95x90Na.
The reaction mixture is adjusted to pH 8.0 with dilute HCl and a precipitate of the compound of formula (I) is obtained. The trisodium 4-carboxy-3-hydroxy-5-mercapto-isothiazole of formula (III) in which R1xe2x95x90R2xe2x95x90R3xe2x95x90Na is an essential intermediate (according to the known art) in the preparation of Cefotetan.
The aforementioned literature also describes the single method currently used to prepare the trisodium 4-carboxy-3-hydroxy-5-mercapto-isothiazole of formula (III) in which R1xe2x95x90R2xe2x95x90R3xe2x95x90Na; this method is very lengthy and impractical and especially requires the use of metal sodium and liquid ammonia, as explained in detail on page 2633 of the aforementioned edition of Chem. Pharm. Bull.
An object of the present invention is therefore to provide, for the preparation of compounds of formula (III), a method which is economically very advantageous compared with the known method, and avoids the use of dangerous substances such as metal sodium and ammonia.
The invention hence relates to a process for obtaining 4-carboxy-3-hydroxy-5-mercapto-isothiazole salts of formula 
in which R1xe2x95x90R2xe2x95x90R3xe2x95x90Na or K; R1xe2x95x90Na or K and R2xe2x95x90R3xe2x95x90H; or R1xe2x95x90R2xe2x95x90Na or K and R3xe2x95x90H, wherein the disodium or dipotassium salt of 3-hydroxy-5-mercapto-4-isothiazole carbonitrile is refluxed in an aqueous solution of sodium hydroxide or potassium hydroxide in a quantity between 3 and 6 equivalents for a time period of at least 15 h, to give an aqueous solution containing the trisodium or respectively tripotassium salt of 4-carboxy-3-hydroxy-5-mercapto-isothiazole (III) in which R1xe2x95x90R2xe2x95x90R3xe2x95x90Na or K, the salt being precipitated from this solution when the solution pH is corrected to a minimum value of about 8 by adding HCl.
In particular the pH of said aqueous solution is adjusted between 8.0 and 8.5 to precipitate the compound of formula (III) in which R1xe2x95x90Na or K and R2xe2x95x90R3xe2x95x90H.
The disodium or dipotassium salt of 3-hydroxy-5-mercapto-4-isothiazole carbonitrile is easily produced with a yield of 97% by reacting the disodium or dipotassium salt of dicyano-1,1-ethylene-dithiol with 30% hydrogen peroxide, as described in U.S. Pat. No. 3,230,229.
The salts of the compound of formula (III) in which R1xe2x95x90Na or K and R2xe2x95x90R3xe2x95x90H are new compounds and also form a subject of the present invention. It is important to note that if Cefotetan is to be produced using the tri-sodium or tri-potassium salt of the compound of formula (III) the pH of the solution of this salt (a strongly basic solution) must be considerably lowered (to about pH 8.5) by large additions of concentrated HCl.
The solutions of the mono-salt and di-salt according to the invention are also of basic pH but much lower, so that these solutions can be used directly without adding HCl or only with a minimum addition of HCl, for direct industrial use in the production of Cefotetan.
In order to clarify the understanding of the characteristics of the present invention, some non-limiting examples are given hereinafter.